Process for the partial elimination of oxo groups in steroids



nited States Patent PROCESS FOR THE PARTIAL ELIMINATION OF OX GROUPS INSTEROIDS Albert Wettstein, Basel, Charles Meystre, Arlesheim, andJean-Ren Billeter, Basel, Switzerland, assignors to Ciba PharmaceuticalProducts, Inc., Summit, N. J.

No Drawing. Application October 7, 1953 Serial No. 384,782

Claims priority, application Switzerland October 15, 1952 11 Claims.(Cl. 260-239.55)

This invention relates to the manufacture of compounds of the steroidseries and more particularly to a process for the partial removal of oxogroups in u-diOXO- compounds of the steroid series, their enols andenolates.

One of the most usual methods for the reductive removal of ox-o groupsis the process of Wollf-Kishner (R. Adams, Organic Reactions, vol. IV,378 (1949)), which has later been modified and improved by Huang-Minlon(J. Am. Chem. Soc. 71, 3301 (1949)). In the latter reaction, thecarbonyl compound is boiled under reflux for about /2 hour in diortri-ethylene glycol together with percent alkali hydroxide and an excessof hydrazine hydrate. Distillation from the product of the solventmixture is then carried out until the residue has a boiling temperatureof about 200 C., whereupon it is further boiled under reflux for severalhours.

Even the described improved modification of the reaction, in the case ofOL-dIOXO-COIDPOUHOS of the steroid series or their enols, especially the11:12-diketones or the A -1l-hydroxy-l2-ketones, leads to diiiicultlyreproducible results for the reason that diflicultly separable mixturesare often produced. The course of the reaction is shown to be veryvariable with small alterations of the reaction conditions. If thereaction temperature is selected only a little too high both oxygenfunctions are eliminated (see, for example, Motlet and Hunter, J. Am.Chem. Soc. 73, 1973, 1951). On the other hand if the reactiontemperature is too low by a small amount there is no removal Whatever ofoxygen functions.

The present invention is based on the surprising observation thatapartial removal of oxo-groups from w dioxo-compounds of the steroidseries, their enols or enolates, can be elfected smoothly and with goodyield when the specified starting materials are heated with hydrazine orits derivatives to above about 160 C. in the absence of basic alkalimetal compounds.

There may be used as starting materials a-dioxocompounds of the steroidseries which contain the two adjacent oxo-groups for example in 2- and3-position, 3- and 4-position, 6 and 7-position, 16- and l7-position,and 21-position and especially l1- and l2-position, or the correspondingenols, such as the A -1l-hydroxy-l2- ketones or A -16-hydroxy-17-ketonesor their enolates, for example metal enolates, enol acylates or enolothers. The steroids may be derived, for example, from the oestrane,androstane, testane, a'etiocholane, pregnane,

spirostane, furostane, bufostane, cholane, cholestane, nore ICE 2 lowboiling solvents, such as low boiling alcohols, for example ethanol,propanol, butanol, hydrocarbons, for example benzene or xylene, ordioxane, under pressure, that is to say in a bomb tube or autoclave, ata temperature above about 160 C. A simple process consists in that thereaction is carried out by heating without pressure in such solvents asboil above about 160 C., such as glycol, di or poly-ethylene glycol,propylene glycol or benzyl alcohol. It is advantageous to heat themixture of starting material, solvent and hydrazine or its derivative,first for about /2 hour to the boiling temperature, which may lie belowabout 160 C., and then to distil oft" a portion of the solution forremoval of the relatively low boiling fractions, such as water orhydrazine,

' and then to heat the residue, in general for a few hours;

for example, about 2 to 6 hours to above about 160 C.

The working up is very simple, for example, by pouring the reactionmixture obtained into water and taking up in a low boiling organicsolvent by steam distillation or by vacuum distillation.

The yields of the reaction products produced by partial removal ofoxo-groups, in contradistinction to the known processes, are very goodand can be reproduced without difliculty. Secondary conversions such asmay otherwise take place easily under the action of'the strong alkalies,are avoided to a far-reaching extent in the present process.

The following examples illustrate the invention, the relation betweenparts by weight and parts by volume being the same as that between thegram and the cubic centimeter:

Example 1 10 parts by weight of3/3-hydroxy-1l:12-diketo-isoallo-spirostane which is present to someextent in theform of the enol, are boiled under reflux for 30 minuteswith 400 parts by volume of glycol and 20 parts by volume of hydrazinehydrate. Then parts by volume of the solvent mixture are distilled oil,the residue boiled for 3 hours under reflux, the cooled solution treatedwith water and the suspension obtained extracted by shaking with anether-chloroform mixture (4:1) and the etherchloroform solution washedwith water, dried and evaporated. From the ether or ether-pentanesolution of the residue, 6.5 parts by weight of3,6-hydroxy-l1-keto-isoallo-spirostane of melting point 216-227 C.crystallize in the form of needles. On recrystallization from methanol,the melting point is raised to 229-232 C.; [a] =29.5 in chloroform.

The starting material was prepared by oxidation of pure 3,8212 dihydroxyl1 keto iso allo spirostane with bismuth trioxide (E 0 in boilingglacial acetic acid and recrystallization only once from methanol.

Example 2 10 parts by weight of3B-hydroxy-1l:12-diketo-isoallo-spirostane which is present partly inthe form of the enol, are boiled under reflux for 30 minutes with 400parts by volume of propylene glycol and 20 parts by volume of hydrazinehydrate. 100 parts by volume of the solvent mixture are then distilledoff and the residue boiled for 6 hours further under reflux. The cooledsolution is worked up as in Example 1, whereby the3B-hydroxy-l1-keto-iso-allo-spirostane is produced in the same quantityand quality.

Example 3 10 parts by weight of3,3-hydroxy-11:12-diketo-iso-allospirostane, which is present in part ofthe form of the enol, are boiled under reflux for 30 minutes with 400parts by volume of diethylene glycol and 20 parts by volume of hydrazinehydrate. Then 100 parts by volume of the solvent mixture are distilledoff. The residue is boiled for a further 2 hours under reflux. Thesolution is then cooled and worked up as in Example 1, whereby the3e-hydroxy-11-keto-iso-allo-spirostane is obtained in the same quantityand quality.

Example 4 10 parts by weight of3,8-hydroxy-11:IZ-diketo-isoallo-spirostane, which is present in part inthe form of the enol, are boiled under reflux for 30 minutes with 400parts by volume of benzyl alcohol and 15 parts by volume of hydrazinehydrate. Thereupon 100 parts by volume of the solvent mixture aredistilled off and boiling continued for a further 2 hours under reflux.The solution is then treated with steam and the non-volatile residuetaken up in an ether-chloroform mixture (4:1). The ether-chloroformsolution is dried and evaporated. By recrystallization of the residuefrom ether or an etherpentane mixture, 6.9 parts by weight are obtainedof the 3,8-hydrxy-1 1-keto-iso-allo-spirostane of melting point 216-227C. which on further recrystallization from methanol is raised to 229-232C.

Instead of hydrazine hydrate semi-carbazide can be used for thereaction, or also corresponding salts such as semi-carbazide acetate orhydrazine sulfate, in which case the equivalent quantity of alkali canbe added as an acid binder.

Example parts by weight of the ll-enol-acetate of 3fl-acetoxy- 11:12diketo-iso-allo-spirostane are boiled under reflux for 30 minutes with10 parts by volume of hydrazine hydrate and 400 parts by volume ofdiethylene glycol. So much of the solvent is now distilled off that theboiling temperature rises to 220-230 C. and then the solution is heatedfor a further 2 hours under reflux. The cooled solution is then treatedwith. Water and the suspension produced extracted by shaking with anetherchloroform mixture (4:1). The ether-chloroform solution is washedwith water, dried and evaporated. The residue is crystallized frommethanol or from isopropyl ether, whereby the 3fi-acetoxy-11-leto-iso-allo-spirostane of melting point 223-227 C. is obtained.

Example 6 parts by weight of A -3e-acetoxy-1l:12-diketo-24:24-diphenyl-cholene, part of which is in the form of the enol, areboiled for minutes under reflux with parts by volume of ethyl alcohol,10 parts by volume of hydrazine hydrate and 160 parts by volume oftriethylene glycol. parts by volume of the solvent mixture are thendistilledoff, and the remainder heated to,

230 C. for another 2 hours, cooled and poured into water. Theprecipitated reaction product is extracted with ether, the etherealsolution washed with Water, dried and evaporated. The residue (18.5parts by weight) is dissolved in 40 parts by volume of pyridine andmixed with 20 parts by volume of acetic anhydride. The solution isallowed to stand for 5 hours at room temperature and then concentratedin vacuo. The acetylation product is taken up in ether, washed withdilute hydrochloric acid, sodium carbonate solution and water, andconcentrated to a small volume. 100 parts by volume of ethyl alcohol areadded, 25 parts by volume are evaporated and the remainder allowed tocool. 13.4 parts by weight of A -3ot-acetoxy-11-keto-24z24-diphenylcholene of melting point 168169 C. crystallize, locl =+77 in dioxane.

I The A 3t;- acetoxy 11:12 diketo 24:24 diphenyl-cholene used asstarting material can be prepared as follows: p

160 parts by weight of bismuth-trioxide, 160 parts by volume of glacialacetic acid and 1500 parts by volume ofchlorobenzene are heated to theboil while stirring and 300 parts by volume of liquid distilled off inthe course of 1 hour until the distillation temperature exceeds 120 C.After this, 71.6 parts by weight of A -3ot-acetoxy- 12B hydroxy 11 keto24:24 diphenyl cholene are dissolved in 50 parts by volume ofchlorobenzene and 300 parts by volume of glacial acetic acid added.While stirring, another 300 parts by volume of solvent are distilled offin the course of 1-1 /2 hours until the distillation temperature exceeds120 C., the color of the reaction mixture changing from white to gray.The mixture is then cooled and filtered, the clear filtrate isevaporated and the residue recrystallized from isopropyl ether. Thereare obtained 48.5 parts by weight of M 61:- acetoxy 11:12 diketo 24:24diphenyl cholene of melting point 142144 (3., lal ==+l00 (c.=1 indioxane).

On evaporation and acetylation of the residue with boiling aceticanhydride the mother liquors yield 19.4 parts by weight of A3a-acetoxy-11:l2-diketo-24:24- diphenyl-cholene-ll-enol acetate ofmelting point 165- 167 C., [a] =-{-125 (c.=l in dioxane).

Example 7 28 parts by weight of 3ot-hydroxy-11: l2-diketo-cholanic acid,part of which is in the form of the enol, are converted into the sodiumsuit by means of parts by volume of normal caustic soda solution and thesolution mixed with 14 parts by volume of hydrazine hydrate and 240parts by volume of triethylene lycol. The whole is boiled for 45minutes, 73 parts by volume of the mixture are distilled off and theremainder heated to 170 C. for 2 hours. It is then allowed to cool, 30parts by volume of concentrated hydrochloric acid are added and 400parts by volume of Water added dropwise in the course of 30 minutes. Theprecipitated reaction product is dissolved in a solution of 5 parts byWeight of sodium hydroxide in 250 parts by volume of water, the solutionstirred for 15 minutes with Hytlo (diatomaceo'us earth filter aid),suction-filtered, and introduced dropwise at C. into parts by volume ofacetic acid and parts by volume of water. There are obtainel 24.7 partsby Weight of 3tx-hydroxy-1l-keto-cholanic acid of melting point 21.52l8C. [m] =+63 (in alcohol).

What is claimed is:

1. A process for the partial removal of oxo-gronps, which comprisesheating a member of the group consisting of an 11,12-diketo-steroid,enols and enolates thereof, said 11,12-diketo-steroid being a member ofthe group consisting of steroids of the oestrane, androstane, testane,aetiocholane, pregnane, spirostane, furostane, bufostane, cholane,cholestane, norand bisnor-cholestane and ergostane series, to atemperature above about C. With a member of the group consisting ofhydrazine and derivatives thereof in the absence of a basic alkali metalcompound.

2. A process according to claim 1, wherein A -11-hydroxy-12-keto-steroids are used as starting material.

3. A process according to claim 1, wherein enolates of A-1l-hydroxy-12-keto-steroids are used as starting material.

4. A process according to claim 1, wherein the reaction is carried outunder pressure with the use of a comparatively low boiling solvent.

5. A process according to claim 1, wherein a solvent is used which boilsabove about 160 C. and the reaction is carried out under atmosphericpressure.

6. A process according to claim 1, wherein the reaction mixture istemporarily heated to a temperature below about 160 C., thecomparatively low-boiling portions are then distilled otf, and theresidue is then heated to above about 160 C.

7. A process which comprises heating 3fi-hydroxy-11:12-diketo-iso-allo-spirostane with a hydrazine at a temperature aboveabout 160 C. and in the absence of a basic alkali compound so as toproduce 3B-hydr0xy-11- keto-iso-allo-spirostane.

8. A process which comprises heating ll-enol-ac'etate of 33-acetoxy-11:12-diketo-iso-allo-spirostane with a hy- 11. A process forthe partial removal of oxo-groups which comprises heating a member ofthe group consisting of an 11,12-diketo-steroid, enols and enolatesthereof, said 11,12-diketo-steroid being a member of the pregnaneseries, to a temperature above about 160 C. With a member of the groupconsisting of hydrazine and derivatives thereof in the absence of abasic alkali metal compound.

References Cited in the file of this patent Organic Reactions, VOL 4,1948, pp 378-415.

1. A PROCESS FOR THE PARTIAL REMOVAL OF OXO-GROUPS, WHICH COMPRISESHEATING A MEMBER OF THE GROUPP CONSISTING OF AN 11, 12-DIKETO-STEROID,ENOLS AND ENOLATES THEREOF, SAID 11,12-DIEKTO-STEROID BEING A MEMBER OFTHE GROUP CONSISTING OF STEROIDS OF THE OESTRANE, ANDROSTANE, TESTANE,AETIOCHOLANE, PREGNANE, SPIROSTANE, FUROSTANE, BUFOSTANE, CHOLANE,CHOLESTANE, NOR- AND BISNOR-CHLOESTANE AND ERGOSTANE SERIES, TO ATEMPERAATURE ABOVE ABOUT 160*C. WITH A MEMBER OF THE GROUP CONSISTING OFHYDRAZINE AND DERIVATIVES THEREOF IN THE ABSENCE OF A BASIC ALKALI METALCOMPOUND.